1. Field of Invention
This invention relates to substituted benzoate ester prodrug derivatives of 3-hydroxymorphinans, pharmaceutical compositions comprising prodrugs of 3-hydroxymorphinans and a suitable pharmaceutical carrier, methods of treating pain or reversing the effects of narcotic drugs such as morphine in a mammal using the prodrug, methods for preparing the prodrug, nitrobenzoate intermediates useful in the preparation of the prodrug, and a method for preparing the intermediates. The prodrugs provide enhanced bioavailability of 3-hydroxymorphinans from orally administered doses.
2. Prior Art
U.S. Pat. No. 3,393,197 issued to Pachter and Matossian on July 16, 1968 disclose N-substituted-14-hydroxydihydronormorphines, including the N-cyclobutylmethyl derivative, commonly called nalbuphine. These compounds combine the properties of being narcotic antagonists as well as analgesics.
Morphine, oxymorphone, hydromorphone, and levorphanol are well known strong narcotic analgesics which can unfortunately be addictive and/or euphoric and are subjected to abuse by parenteral administration.
Heretofore many compounds have been prepared which have the 3-hydroxymorphinan ring nucleus, including several derivatives having various substituents on the nitrogen atom thereof. It has also been found that these compounds not only have analgetic properties but some have narcotic antagonist properties.
U.S. Pat. No. 3,254,088 issued to Lewenstein on May 31, 1966 discloses N-allyl-7,8-dihydro-14-hydroxynormorphinone commonly known as naloxone. U.S. Pat. No. 3,332,950 issued to Pachter and Matossian on July 25, 1967, discloses N-substituted-14-hydroxydihydronormorphinones including the N-cyclopropylmethyl analog commonly known as naltrexone. Compounds of these two patents are narcotic antagonists.
The definition of narcotic antagonism adopted in the present invention is that of Archer and Harris, in their Chapter on this topic in Progress in Drug Research, Vol. 8, 1965, pages 261 to 320, wherein narcotic antagonists are defined as compounds which "have the remarkable property of reversing the major pharmacodynamic actions of the narcotics . . . . Strictly speaking we consider a substance to be a narcotic antagonist if it can reverse the more prominent effects of morphine such as analgesia, sedation, respiratory depression and myosis."
German Pat. No. 2,323,192 issued to Endo Labs, Inc. on Apr. 26, 1973 discloses long-acting injectable narcotic antagonist preparations consisting essentially of a compound of the formula ##STR1## wherein: R is allyl or cyclopropyl methyl,
R.sup.1 includes benzoyl or substituted benzoyl, PA1 R.sup.2 is H or R.sup.1, and PA1 X is O or a ketal, PA1 R is methyl, allyl, methylallyl, cyclopropylmethyl, or cyclobutylmethyl; PA1 R.sup.1 is hydrogen, or OH; PA1 R.sup.2 is hydrogen, OH, or =O; PA1 R.sup.3 and R.sup.4 are hydrogen, or taken together are --O- - -; PA1 R.sup.5 is t-butyl or n-propyl; PA1 X and Y are individually selected from H, OR.sup.6, NHR.sup.6 and NR.sup.6 R.sup.7, provided that at least one of X or Y is OR.sup.6, NHR.sup.6, or NR.sup.6 R.sup.7 ; PA1 R.sup.6 is H, C.sub.1 -C.sub.4 alkyl, or COR.sup.8 ; PA1 R.sup.7 is C.sub.1 -C.sub.4 alkyl, or COR.sup.8 ; and PA1 R.sup.8 is H, or C.sub.1 -C.sub.4 alkyl. PA1 R-R.sup.8 are as defined above; and PA1 Y.sup.1 is selected from H, OR.sup.6 or NR.sup.6 R.sup.7. PA1 nalbuphine-3-anthranilate hydrochloride (X=2--NH.sub.2.HCl, Y=H) PA1 nalbuphine-3-(acetylsalicylate) (X=2--CH.sub.3 CO.sub.2, Y=H) PA1 nalbuphine-3-(N-methylanthranilate)hydrochloride (X=2--NHCH.sub.3.HCl, Y=H) PA1 nalbuphine-3-(2,4-dimethoxybenzoate) (X=2--CH.sub.3 O, Y=4--CH.sub.3 O) PA1 nalbuphine-3-salicylate (X=2--OH, Y=H) PA1 naltrexone-3-anthranilate (X=2--NH.sub.2, Y=H) PA1 naloxone-3-anthranilate (X=2--NH.sub.2, Y=H) PA1 butorphanol-3-anthranilate (X=2--NH.sub.2, Y=H) PA1 buprenorphine-3-anthranilate hydrochloride (X=2--NH.sub.2.HCl, Y=H) PA1 buprenorphine-3-(acetylsalicylate) (X=2--CH.sub.3 CO.sub.2, Y=H) PA1 buprenorphine-3-salicylate hydrochloride (X=2--OH, Y=H)
and a vegetable oil suitable for subcutaneous or intramuscular administration. This patent further discloses that the duration of narcotic antagonist activity for the preparations in vegetable oil is prolonged as compared to the corresponding aqueous preparations. This patent also discloses the reaction of N-substituted-7,8-dihydro-14-hydroxynormorphinones with one equivalent of an acid chloride (R.sup.5 COCl) in the presence of a base, such as an alkali carbonate or bicarbonate, or in the presence of a tertiary amine, such as pyridine or triethylamine. ##STR2##
Venuti, Synthesis, 266 to 268 (1982), discloses the reaction of isatoic anhydride with a variety of simple amines and alcohols in the presence of 4-dimethylaminopyridine to prepare anthranilamides and anthranilate esters. Only monofunctional alcohols and amines are used, and the use of substituted isatoic anhydrides in the reaction is not disclosed.
The oral administration of many drugs will elicit a substantially lesser response as compared to an equal dosage administered parenterally. This reduction in potency most commonly results from the extensive metabolism of the drug during its transit from the gastrointestinal tract to the general circulation. For example, the liver and intestinal mucosa, through which an orally administered drug passes before it enters the circulatory system, are very active enzymatically and can thus metabolize the drug in many ways.
When an orally administered drug is metabolized rapidly by the gastrointestinal system or liver prior to entering the circulatory system, its bioavailability is low. In certain instances, this problem can be circumvented by administering the drug by another route. Examples of such alternative routes include nasal (propanalol), sublingual (nitroglycerin) or inhalation (cromolyn sodium). Drugs administered by these routes avoid hepatic and gut-wall metabolism on their way to the systemic circulation.
In some instances, the presystemic metabolism of certain orally administered drugs can be overcome by derivatization of the functional group in the molecule that is susceptible to gastrointestinal hepatic metabolism. This modification protects the group from metabolic attack during the absorption process or first pass through the liver. However, the masking group must ultimately be removed to enable the drug to exert its maximum effect. This conversion may take place in blood or tissue. These types of masked drugs are usually referred to as prodrugs.
A desired characteristic of a prodrug is that it is pharmacologically and toxicologically inert until cleaved into its two components. Also, it is important that the chemical group used to alter the parent drug be relatively non-toxic, since it will eventually be released in the body.
There are a number of examples in the literature which demonstrate the feasibility of the prodrug concept. However, it is apparent from these published studies that each drug class must be considered by itself. There is no way to accurately predict which prodrug structure will be suitable for a particular drug. A derivative which may work well for one drug may not do so for another. Differences in absorption, metabolism, distribution, and excretion among drugs do not permit generalizations to be made about prodrug design.
Many of the above 3-hydroxymorphinans are potent narcotic antagonist and/or analgesics which undergo extensive gastrointestinal and/or first pass metabolism upon oral delivery, and thus have decreased bioavailability. None of the references cited, nor any known references, suggest the novel substituted benzoate esters of 3-hydroxymorphinans of the instant invention, or their desirability as prodrugs of 3-hydroxymorphinans.